Aim: The aim of this systematic review was to identify studies that examined maxillary lateral incisor agenesis treatment, by either orthodontic space closure by canine mesial repositioning and reshaping, or by a prosthodontic intervention, in order to compare the biological, functional and aesthetic outcomes of these two approaches. Materials and methods: An electronic MEDLINE search was conducted by two independent reviewers in order to isolate English language articles, published in scientific journals between January 1975 and March 2015, reporting on treatment of agenesis of maxillary lateral incisors, accomplished either by canine orthodontic repositioning or prosthodontic intervention. The search terms were categorised into the four groups comprising the PICO (problem, intervention, comparison and outcome) question. Supplementary manual searches of published reviews and other full-text articles were also performed. Results: The initial database search produced 8,453 titles. After careful examination and discussion, 12 articles were selected for inclusion, where 5 of them compared the two therapeutic options directly. No randomised controlled trials were identified. Conclusions: Definitive conclusions cannot be drawn, since randomised controlled trials and more prospective and retrospective studies directly comparing the two therapeutic options are required. According to this systematic review, both therapeutic options are effective. However, it seems that the orthodontic space closure, whenever this is possible, is advantageous over the prosthodontic rehabilitation.